study, we were surprised that higher borylation tempera-
tures gave lower product yields. The favorable temperature
range was found to be 70–908C (Table 1, entries 1–4, and
see the Supporting Information for the reaction temperature
probing).[10] A screening of commonly used inorganic and
organic bases indicated that KOAc and Et3N were both suit-
able bases for this coupling reaction (Table 1, entry 2 vs. en-
tries 5–9). However, by using an organic base the homoge-
neous conditions would offer several advantages for flow
system/microchannel reactors. Stronger bases such as K3PO4
À
and K2CO3 undesirably promoted further C C coupling re-
action giving symmetrical biaryl side products. The Pd/L
ratio of 1:4 showed the best yield whereas ratios of 1:3 and
1:2 provided slightly lower substrate conversions (Table 1,
entry 2 vs. 10 and 11). The solvent tBuOH gave the best
result (Table 1, entry 2 vs. entries 12–17). Although complete
conversion was observed in MeOH solvent, a substantial
amount of tert-butylbenzene side product was observed
(Table 1, entry 13). The effectiveness of the boron source
was then investigated. The stoichiometry of the electrophile
and borylating agent used in the reaction also affected the
product yield (Table 1, entry 2 vs. 18), however, the use of
bis(pinacolato)diboron (B2pin2) as the limiting agent provid-
ed a slightly better yield. B2pin2 provided the best result,
whereas bis(neopentyl glycolato)diboron afforded a satisfac-
tory product yield (Scheme 1). However, the catechol ester
provided the product in a poor yield and pinacol borane es-
sentially gave no reaction in this catalytic system.
Scheme 2. Ligand development and investigation in Pd-catalyzed borylation of
aryl tosylate. Reaction conditions: aryl tosylate (ArOTs, 0.75 mmol), bis(pina-
colato)diboron (B2pin2, 0.5 mmol, limiting reagent), KOAc (1.5 mmol), Pd-
AHCTUNRTGEG(NUNN OAc)2/Ligand=1:4, and tBuOH (1.5 mL) were stirred at 908C for 2 h under
nitrogen. Parentheses indicate the yield of reactions. PCy2 = dicyclohexylphos-
phino.
phine based on the CM-phos scaffold, yet without seriously
affecting the ligand template, to facilitate the oxidative addi-
À
tion in C B bond coupling. We thus introduced a MeO
group at the para-position to the PCy2 moiety to give a new
ligand MeO-CM-phos (Scheme 2). To our delight, a com-
plete conversion of aryl tosylate was observed when the new
ligand was applied.
With the new Pd/MeO-CM-phos system in hand, next we
investigated the scope of borylation of aryl tosylates. A wide
range of activated and non-activated aryl tosylates were ex-
amined (Table 2). Common functional groups such as ni-
triles, keto, ester, aldehyde, and benzodioxolyl were compat-
ible under these mild reaction conditions (Table 2, entries 1–
7). These corresponding arylboronic acids are expensive and
not readily available. In general, the reactions were com-
plete within 2 h in the presence of Pd catalyst (1–2 mol%).
Quinolyl and unprotected indolyl substrates showed good
product yields in the borylation (Table 2, entries 8 and 10).
Notably, 3-aminophenyl tosylate gave the desired product in
excellent yield and the free NH2 group remained intact
(Table 2, entry 9).
Scheme 1. An investigation of the efficiency of boron sources.
To further evaluate the versatility of the new catalytic
system, we shifted our attention to the viability of aryl me-
sylates. In fact, aryl mesylates are even less reactive than the
corresponding aryl tosylates in coupling reactions[13] and
they have proven to be a difficult substrate in oxidative ad-
dition. Yet, they are more atom-economical than tosylates.
Inspired by this advantage, we tested our new catalytic
system in the borylation of aryl mesylates (Table 3).
Relative to aryl tosylate borylation, a variety of common
functional groups were well tolerated. The functionalized
aryl mesylates containing nitriles, keto, ester, aldehydes, and
benzodioxolyl groups were borylated in good to excellent
yields (Table 3, entries 1–6 and 12). In addition to function-
alized aryl mesylates, deactivated and heteroaryl mesylates
were also effective coupling partners; quinolyl and benzo-
thiazolyl mesylates gave good yields of the corresponding
coupling products (Table 3, entries 10 and 11), whereas
After detailed reaction parameter screenings, we still
found that an additional 15–20% of unreacted aryl tosylate
remained in the reaction. We believed that this ligand
system may not be effective in oxidative addition of ArOTs
under the mild reaction conditions, especially at 70–908C.
Thus we re-examined the efficacy of our indolyl ligand
family for this reaction (Scheme 2). Aminophosphine L1[11]
gave no conversion of aryl tosylate. Surprisingly, we found
this borylation reaction is highly sensitive to the position of
the phosphino group on the indolyl scaffold. When the dicy-
clohexylphosphino (PCy2) group was located at the C-3 po-
sition of the indole ring (i.e., L2),[12] essentially no reaction
was attained. On the contrary, a dramatic increase of sub-
strate conversion was observed when the CM-phos ligand
was employed. In view of the suitability of this ligand tem-
plate, we attempted to design a more electron-rich phos-
6914
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Chem. Eur. J. 2011, 17, 6913 – 6917